Drug Design And Biological Application Of Novel Thioredoxin Reductase Inhibitors

The thioredoxin(Trx)system(including NADPH,TrxR,and Trx)is one of the major cellular antioxidant pathways that control redox homeostasis.Among them,TrxR has a unique C-terminal-Gly-Cys-Sec-Gly active site which is extremely susceptible to binding by electrophilic reagents.TrxR is closely associated with tumor proliferation,invasion,apoptosis,drug resistance,recurrence and metastasis.Therefore,TrxR has become a significant target for tumor recurrence/metastasis and anticancer drug development.Inhibition of TrxR leads to decreased activity of thioredoxin-dependent enzymes and reduced scavenging of reactive oxygen species(ROS),resulting in oxidative stress,apoptosis and necrosis.Given the high failure rate of new drug clinical studies in recent years,"Drug repurposing" has become an attractive and new strategy to optimize cost/benefit for pharmaceutical companies."Drug repurposing" is not limited to existing marketed drugs,but should also include potential candidates that were/are in preclinical or clinical studies.In this paper,two types of TrxR small molecule inhibitors have been synthesized and their potential mechanisms of action have been investigated with the strategy of " Drug repurposing" as follows:Chapter 1: Introduction.This chapter provides an overview of the role of the Trx system and some of the classical TrxR inhibitors,and describes the advantages and challenges of the " Drug repurposing " strategy.Chapter 2: Synthesis of acetaminophen(APAP)analogs and their antitumor mechanisms.Twenty-five compounds were synthesized based on the modification of the basic structure of APAP.A8 with two Br atomic substituents,which is the most toxic to HeLa cells,was selected.Next,a series of biological experiments were conducted to test the mechanism of action of A8 using several experiments,which showed that A8 can inhibit TrxR activity in HeLa cells and can induce oxidative stress through its effect on GSH,and finally induce apoptosis in HeLa cells.These data suggest an alternative mechanism for the anticancer activity of APAP and provide a basis for further studies on the interaction between APAP analogs and TrxR.Chapter 3: Synthesis of quinolone analogs and study of their antitumor mechanism.Twenty-five compounds were synthesized based on the modification of the basic structure of quinolones.The most toxic to HepG2 cells,B5 with a nitro substituent,was screened.Next,a series of biological experiments were conducted to test the mechanism of action of B5,which showed that B5 could inhibit TrxR activity in HepG2 cells and induce oxidative stress through its effect on GSH,and finally induce apoptosis in HepG2 cells.These experiments validated a possible pathway of action of quinolones to induce apoptosis by inhibiting TrxR causing an increase in the level of ROS in HepG2 cells.Chapter 4: Summary and outlook.The full text is summarized and prospects for further synthesis and biological applications of APAP and quinolones are provided.